Sensory defects are a major human health concern. While defects can often occur at the level of sensory detection, these processes can also fail at the level of sensory integration. Therefore, it is essential to understand sensory signaling at bot the level of detection and integration. Chemical signals, such as small molecule pheromones and kairomones, are used by humans and most other animals to communicate with and respond to their environment. These chemicals can elicit very different responses depending on the external (environmental influences) or internal state of the recipient. Although this response flexibility is critical for animal survival, the neural mechanisms that contribute to this adaptabiity are not well understood. To understand this process, one must identify the site(s) of signal integration of multiple stimuli and subsequently determine how these signals converge to promote novel responses. Due to its experimental amenability, these mechanisms can be identified in the nematode, C. elegans, which uses conserved chemical signal transduction complexes in sensory neurons. Identification of the mechanisms of signal integration in C. elegans will not only improve methods for the diagnosis and treatment of chemosensory disorders, but will also lead to new strategies to control parasitic nematodes through interference with pheromone signaling. To identify mechanisms of sensory signal integration, this proposal focuses on two conserved ascaroside (ascr) pheromones, ascr#3 and ascr#9, which produce sexually-dimorphic (intrinsic) and context-specific (environmental) behavioral responses. Aim 1: Determine the genetic, molecular and neural basis of ascr#3-dependent sexually-dimorphic signaling in adult animals. Sexually dimorphic behavioral responses to ascr#3 require sensory input from the ADL chemosensory neurons via largely undefined molecular mechanisms. Preliminary data indicate that these sexually dimorphic behaviors may be due to differences in neuronal sex, and that a member of the SRBC family of G-protein coupled receptors may encode ascr#3-specific receptors in ADL. This proposal will identify and characterize the first adult-specific chemoreceptor(s) and signaling molecules that regulate ascr#3-dependent C. elegans adult behaviors and determine the basis of sexually dimorphic responses to ascr#3. Aim 2: Identify the role of ascr#9 in dauer larval avoidance behavior in combination with other pheromone cues. Under limited resources, many nematodes enter an alternative developmental stage, termed the dauer larva, that facilitates dispersal (in free living nematodes) and infection (in parasitic nematodes). The conserved pheromone ascr#9 directs avoidance behavior in dauer larvae of several species when presented in combination with other ascr cues, providing an excellent model for combinatorial sensory input. This proposal will specifically determine the neural basis of combinatorial effects of ascr#9 on larval avoidance and identify molecular mechanisms of ascr#9-dependent signaling through the analysis of natural variation in wild C. elegans strains.